Integrating Tumor Biology and Host Factors in mCRPC: The Prognostic Value of ‘Time to Castration Resistance’, Systemic Inflammation, and Comorbidity Burden in Patients Treated with Enzalutamide

TL;DR

This study shows that tumor-related factors like metastasis and treatment timing are more important than patient health in predicting outcomes for prostate cancer patients on enzalutamide.

Contribution

The study highlights the importance of tumor biology and treatment timing over host factors in predicting survival in mCRPC patients treated with enzalutamide.

Findings

Visceral metastasis increases the risk of death by 4.0-fold in mCRPC patients.

High skeletal tumor burden is associated with a 5.5-fold increase in mortality risk.

Delays in starting enzalutamide increase the risk of death by 7.3% per month.

Abstract

Background: Outcomes with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) are influenced by tumor burden, disease kinetics, and host factors. We evaluated the relative prognostic impact of metastatic pattern, laboratory markers, and prostate-specific antigen (PSA) dynamics in a real-world cohort. Methods: We retrospectively analyzed 72 patients with mCRPC treated with enzalutamide. Progression-Free Survival (PFS) and Overall Survival (OS) were estimated using the Kaplan–Meier method. Multivariate Cox proportional hazards models were utilized to identify independent predictors of survival, incorporating clinical variables (visceral metastases, bone tumor burden), kinetic parameters (Time to Castration Resistance [TTCR], Time to PSA Nadir [TTN]), and host factors (Charlson Comorbidity Index [CCI], Eastern Cooperative Oncology Group Performance Status (ECOG PS), Systemic Immune-Inflammation Index [SII], HALP score). Results: Visceral metastasis was a dominant predictor of poor outcomes, increasing the risk of death by 4.0-fold (HR: 4.05; 95% CI: 1.84–8.89; p < 0.001). A high skeletal tumor burden (≥5 bone lesions) was identified as a critical threshold, associated with a 5.5-fold increase in mortality risk (HR: 5.53; p < 0.001). Delays in initiating enzalutamide significantly compromised survival, with each 1-month delay increasing the risk of death by 7.3% (HR: 1.07; p = 0.003). While early PSA decline (≥50% at 3 months) did not independently predict OS, a prolonged TTN (>12 months) was associated with superior survival. Notably, host-related factors, including age, CCI, and ECOG PS, were not found to be significantly associated with survival outcomes in this specific dataset. Conclusions: Our preliminary findings suggest that survival in real-world mCRPC patients treated with enzalutamide may be influenced predominantly by intrinsic tumor biology—specifically anatomical extent and resistance kinetics—rather than host frailty or comorbidity burden. However, given the retrospective and single-center nature of this study, these findings should be considered hypothesis-generating and require validation in larger, multi-center cohorts. Host-related variables (including age and CCI) were evaluated but were not retained as independent predictors in the final multivariable model. Early initiation of therapy and monitoring of kinetic markers like TTN and TTCR offer superior prognostic stratification compared to static baseline characteristics.

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